1. Field of the Invention
This invention relates to various 2-imidazoline, 2-oxazoline, 2-thiazoline, and 4-imidazole derivatives of methylphenyl, methoxyphenyl, and aminophenyl alkylsulfonamides and ureas, and their use in the treatment of various disease states, such as urinary incontinence, nasal congestion, priapism, depression, anxiety, dementia, senility, Alzheimer's, deficiencies in attentiveness and cognition, and eating disorders such as obesity, bulimia, and anorexia.
2. Urinary Incontinence
The lower urinary tract consists of the urinary bladder and urethra. Normal lower urinary tract function requires a coordinated relaxation of the bladder (detrusor muscle) and increase in urethral smooth muscle tone during bladder filling. The expulsion of urine (micturition), in contrast, requires a coordinated contraction of the detrusor and relaxation of urethral smooth muscle. This coordination is achieved by the integration of afferent (sensory) and efferent (parasympathetic, sympathetic, and somatic) nerve activity in both the central and peripheral nervous centers.
Incontinence is a condition characterized by the involuntary loss of urine, which is objectively demonstrable. It is both a social and hygienic problem. Stated simply, incontinence results from the failure of the bladder and/or the urethra to work properly, or when the coordination of their functions is defective. It is estimated that at least ten million Americans suffer from incontinence. While the prevalence of incontinence is two-fold higher in females, with the greatest incidence in postmenopausal women, it also affects males.
Urinary incontinence can be classified into four basic types.
Urge incontinence (detrusor instability) is the involuntary loss of urine associated with a strong urge to void. This type of incontinence is the result of either an overactive or hypersensitive detrusor muscle. The patient with detrusor overactivity experiences inappropriate detrusor contractions and increases in intravesical pressure during bladder filling. Detrusor instability resulting from a hypersensitive detrusor (detrusor hyperreflexia) is most often associated with a neurological disorder.
Genuine stress incontinence (outlet incompetence) is the involuntary loss of urine occurring when increases in intra-abdominal pressure cause a rise in intravesical pressure which exceeds the resistance offered by urethral closure mechanisms. Stress incontinent episodes can result from normal activities such as laughing, coughing, sneezing, exercise, or, in severe stress incontinent patients, standing or walking. Physiologically, stress incontinence is often characterized by a descensus of the bladder neck and funneling of the bladder outlet. This type of incontinence is most common in multiparous women, as pregnancy and vaginal delivery can cause loss of the vesicourethral angle and damage to the external sphincter. Hormonal changes associated with menopause may exacerbate this condition.
Overflow incontinence is an involuntary loss of urine resulting from a weak detrusor or from the failure of the detrusor to transmit appropriate signals (sensory) when the bladder is full. Overflow incontinent episodes are characterized by frequent or continuous dribbling of urine and incomplete or unsuccessful voiding.
Functional incontinence, in contrast to the types of incontinence described above, is not defined by an underlying physiological dysfunction in the bladder or urethra. This type of incontinence includes the involuntary loss of urine resulting from such factors as decreased mobility, medications (e.g., diuretics, muscarinic agents, or alpha.sub.1 -adrenoceptor antagonists), or psychiatric problems such as depression.
The treatment of incontinence depends upon the type and severity. Of the four types of incontinence, pharmacotherapy is most effective in the treatment of urge incontinence. A variety of pharmacological agents such as anticholinergics, smooth muscle relaxants, calcium channel antagonists, and beta-adrenoceptor agonists are used to decrease the contractility of the bladder. Some patients appear to benefit from estrogen (postmenopausal women) and alpha.sub.1 -adrenoceptor agonists. These agents, however, most likely act at the level of the urethra to increase closure pressure and prevent the loss of urine.
Mild to moderate stress incontinence can be treated both pharmacologically and by conservative approaches such as physiotherapy (Kegel exercises) and functional electrical stimulation, both of which aim to strengthen the peri-urethral musculature. Surgery is indicated in severe stress incontinent patients. Surgical techniques seek to improve the alignment of the bladder, urethra, and surrounding structures.
Only a limited number of pharmaceutical agents have been employed, with varying success, to treat stress incontinence. In postmenopausal women, estrogen replacement therapy is thought to improve continence by increasing urethral length and mucosal thickness, thereby increasing urethral closure pressure. Estrogen may also contribute to an increase in alpha.sub.1 -adrenoceptor expression in urethra (Wein, Urologic Clinics of North America (1995) 22:557-577). The efficacy of estrogen therapy is not universally accepted.
Phenylpropanolamine and psuedoephrine are considered first-line therapy for mild to moderate stress incontinence (Wein, supra; Lundberg (editor), JAMA (1989) 261(18):2685-2690). These agents are believed to work both by direct activation of alpha.sub.1 -adrenoceptors and indirectly by displacement of endogenous norepinephrine from sympathetic neurons following uptake into the nerve terminal (Andersson and Sjogren, Progress in Neurobiology (1982) 19:71-89). Activation of alpha.sub.1 -adrenoceptors located on the smooth muscle cells of the proximal urethra and bladder neck (Sourander, Gerontology (1990) 36:19-26; Wein, supra) evokes contraction and an increase in urethral closure pressure.
The utility of phenylpropanolamine and pseudoephrine is limited by a lack of selectivity among the alpha.sub.1 -adrenoceptor subtypes and by the indirect action of these agents (i.e. activation of alpha.sub.1 -, alpha.sub.2 -, and beta-adrenoceptors in the central nervous system and periphery). As a result, any desired therapeutic effect of these agents may be accompanied by undesirable side effects such as an increase in blood pressure. The increase in blood pressure is dose-dependent and therefore limits the ability to achieve therapeutically effective circulating concentrations of these agents (Andersson and Sjogren, supra). Furthermore, in some patients these agents produce insomnia, anxiety, and dizziness as a result of their central nervous system stimulant actions (Andersson and Sjogren, supra; Wein, supra).
Midodrine is a sympathomimetic agent which has been evaluated for the treatment of stress incontinence. This alpha.sub.1 -adrenoceptor agonist is a prodrug which is converted in vivo to the active phenylethylamine, ST-1059. The clinical efficacy of midodrine has not been demonstrated conclusively (Andersson and Siogren, supra). Like the above compounds, its beneficial effects may be limited by cross-reactivity with other adrenoceptors which may limit the maximum achievable dose. A better understanding of alpha.sub.1 -adrenoceptor subtypes and their involvement in various physiological processes may facilitate the development of more efficacious drugs for the treatment of both stress and possibly urge incontinence.
Alpha.sub.1 -adrenoceptors are specific neuroreceptor proteins located in the peripheral and central nervous systems and on tissues throughout the body. The receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development. Drugs which interact at these receptors comprise two main classes: agonists, which mimic the endogenous ligands (norepinephrine and epinephrine) in their ability to activate the adrenoceptors; and antagonists, which serve to block the actions of the endogenous ligands.
During the past 15 years, a more precise understanding of alpha-adrenoceptors and drugs targeting alpha-adrenoceptors has emerged. Prior to 1977, only one alpha-adrenoceptor was known to exist. Between 1977 and 1986, it was accepted by the scientific community that at least two alpha-adrenoceptors, alpha.sub.1 - and alpha.sub.2 -, existed in the central and peripheral nervous systems. New techniques have led to the identification of distinct adrenoceptor proteins which are distributed throughout the central and peripheral nervous systems.
To date, three human alpha.sub.1 -adrenoceptors have been cloned (alpha.sub.1A, alpha.sub.1B, and alpha.sub.1D), expressed, and characterized pharmacologically (Hieble, et al., Pharmacol. Revs. (1995) 47:267-270). The absence of an alpha.sub.1C -adrenoceptor appellation is a consequence of the history of alpha.sub.1 -adrenoceptor subclassification. In 1990, an alpha.sub.1 -adrenoceptor was cloned and designated the alpha.sub.1C -adrenoceptor, as the mRNA for this clone could not be detected in animal tissues known to express pharmacologically-defined alpha.sub.1A -adrenoceptors (Schwinn, et al, J. Biol. Chem. (1990) 265:8183-8189). The alpha.sub.1C -adrenoceptor was later equated with the alpha.sub.1A -adrenoceptor, resulting in the discontinuation of the alpha.sub.1C designation (Ford, et al., Trends Pharmacol. Sci. (1994) 15:167-170).
A fourth subtype, the alpha.sub.1L -adrenoceptor, has been described pharmacologically, but a distinct gene product has not been found (Flavahan and Vahnoutte, Trends Pharmacol. Sci. (1986) 7:347-349; Muramatsu, et al., Br. J. Pharmacol. (1990) 99:197-201). Despite a preponderance of alpha.sub.1A -adrenoceptor mRNA in lower urinary tract tissues, it is the antagonist "fingerprint" of the pharmacologically-defined alpha.sub.1L -adrenoceptor that correlates best with the alpha.sub.1 -adrenoceptor mediating contraction of lower urinary tract smooth muscle (Ford, et al., Mol. Pharmacol. (1996) 49:209-215). Recently, insights into this apparent discrepancy have been made while studying the functional responses in cells transfected with the cloned alpha.sub.1A -adrenoceptor.
In contrast to radioligand binding studies which are traditionally conducted in hypotonic buffers at sub-physiological temperatures, functional studies in transfected cells have been conducted in a physiological buffer at physiological temperature. Using these conditions, the pharmacology of key antagonists closely resembled that of the alpha.sub.1L -adrenoceptor (Ford, et al., Br. J. Pharmacol. (1997) 121:1127-1135). Thus, it appears that the cloned alpha.sub.1A -adrenoceptor can express two distinct pharmacologies (alpha.sub.1A - and alpha.sub.1L -), depending upon the experimental conditions employed. It should be noted that this phenomenon is specific for the alpha.sub.1A -adrenoceptor subtype, as altering the experimental conditions in a similar fashion does not alter the pharmacology of cloned alpha.sub.1B - or alpha.sub.1D -adrenoceptors (Ford, et al.,1997, supra). Until this observation is confirmed and the nomenclature of alpha.sub.1 -adrenoceptors resolved, it would seem prudent to refer to ligands selective for the cloned alpha.sub.1A -adrenoceptor as alpha.sub.1A/1L selective unless selectivity for the alpha.sub.1A or alpha.sub.1L states can be demonstrated.
The precise role of each of the alpha.sub.1 -adrenoceptor subtypes in various physiological responses is only beginning to be understood, but it is clear that individual subtypes do mediate distinct physiological responses to agonists and antagonists. For example, it has been shown that norepinephrine-induced contractions of the human prostate are mediated by the cloned alpha.sub.1A -adrenoceptor (pharmacological alpha.sub.1L -adrenoceptor; Forray, et al, Mol. Pharmacol. (1994) 45:703-708; Ford, et al., Mol. Pharmacol. (1996) 49:209-215).
The role of the sympathetic adrenergic nervous system in the storage function of the bladder is well recognized (Wein, supra; Latifpour, et al., J. Pharmacol Exp. Ther. (1990) 253:661-667). Likewise, it is understood in the art that the study of adrenoceptor mechanisms in isolated urethra and bladder tissues is applicable to incontinence therapy (Latifpour, et al., supra; Tsujimoto, et al., J. Pharmacol. Exp. Ther. (1986) 236:384-389). Various groups have attempted to identify, through radioligand binding and functional studies, the alpha.sub.1 -adrenoceptor subtype(s) in urethrae of humans, rabbits, and rats (Yoshida, et al., J. Pharmacol. Exp. Ther. (1991) 257:1100-1108; Testa, et al., supra; Chess-Williams, et al., J. Auton. Pharmacol. (1994) 14:375-381). These efforts have, thus far, failed to provide conclusive evidence for a particular alpha.sub.1 -adrenoceptor subtype being responsible for the effects of adrenoceptor agonists in the urethra. It is also known that some alpha.sub.1A -adrenoceptor (formally alpha.sub.1C) agonists may be useful for the treatment of urinary incontinence (Craig, et al., WO 96/38143).
Nasal Congestion
Approximately one-half of the resistance to airflow into the lung is provided by the nose and nasal cavity (Proctor, Am. Rev. Resp. Dis. (1977) 115:97-129). The nasal cavity is lined by a continuous mucus membrane which is highly vascularized. Nasal mucosa vascular beds consist of precapillary resistance vessels, venous sinusoids comprising both circular and longitudinal smooth muscle bundles which drain into postcapillary venules, and arteriovenous anastomoses which allow blood to bypass the capillary-sinusoid network (Proctor, et al., Pharmac. Ther. B (1976) 2:493-509; Scadding, Clin. Exp. Allergy (1995) 25:391-394). This anatomical arrangement makes the nasal mucosa, especially that lining the middle and inferior turbinates and septum, erectile tissue (Proctor, et al., 1976, supra). Engorgement of venous erectile tissue alters airway resistance and is important to the functioning of the nose as an air conditioner.
Both resistance and capacitance vessels in the nasal mucosa are richly innervated with autonomic fibers. It has been known for several decades that alpha-adrenoceptors mediate contraction of nasal mucosa (Proctor, et al., 1976, supra). Indeed this has formed the basis of treatment of nasal congestion with sympathomimetic drugs. Subsequent to the identification of distinct alpha-adrenoceptor subtypes (Langer, Biochem. Pharmacol. (1974) 23:1793-1800), the presence of postjunctional alpha.sub.1 - and alpha.sub.2 -adrenoceptors have been shown in nasal mucosa (Ichimura, et al., Arch Otorhinolaryngol (1988) 245:127-131; Andersson, et al., Ann. Otol. Rhinol. Laryngol. (1984) 93:179-182). The presence of prejunctional inhibitory alpha.sub.2 -adrenoceptors has also been shown (Ichimura, et al., Arch Otolaryngol (1984) 10:647-651.) Both alpha.sub.1 - and alpha.sub.2 -adrenoceptors are thought to mediate vasoconstriction of nasal mucosa capacitance vessels (venous sinusoids), whereas only alpha.sub.2 -adrenoceptors are thought to mediate vasoconstriction of resistance vessels (Andersson, et al., supra; Scadding, supra). It is believed that constriction of capacitance vessels reduces nasal congestion directly by increasing the tone of the venous sinusoids whereas constriction of resistance vessels results in an indirect decrease in nasal congestion by increasing arterial resistance and thereby decreased filling of the venous sinusoids (Lung, et al., J. Physiol. (1984) 349:535-551).
Intranasal sympathomimetic agents used to treat nasal congestion fall into two basic chemical classes, namely certain .beta.-phenylethylamines and imidazolines (Empey, et al., Drugs (1981)21:438-443). The non-selective alpha.sub.1 -adrenoceptor agonist, phenylephrine (Minneman, et al., Mol. Pharmacol. (1994) 46:929-936), and the mixed alpha.sub.1 /alpha.sub.2 -adrenoceptor agonist, oxymetazoline (Minneman, et al., supra), are currently used respresentatives of these chemical classes, respectively.
The greatest concern with intranasal sympathomimetics is rhinitis medicamentosa, a syndrome of "rebound" congestion associated with frequent and prolonged use (more than 7 to 10 days). Rhinitis medicamentosa is not a problem with oral decongestants but there is a greater risk of systemic side effects (Empey, et al., supra). Despite the prevelance of this syndrome, the exact cause has not been elucidated. Possible explanations for "rebound" include the following. Prolonged or preferential constriction of the resistance vessels, possibly mediated by alpha.sub.2 -adrenoceptors, may deprive nasal mucosa of oxygen and nutritients thereby resulting in a reactive hyperemia which leads to the release of vasoactive mediators to counteract the vasoconstriction (Berridge, et al., Br. J. Pharmacol. (1986) 88:345-354; Scadding, supra). Prolonged exposure to high concentrations of highly efficacious adrenergic agents may also cause down regulation or desensitization of adrenergic receptors. That is, a decrease in the number or sensitivity of adrenergic receptors could reduce the responsiveness to both exogenous and endogenous sympathomimetics (Scadding, supra). Chemical irritation caused by the active ingredient or an ingredient in the formulation could also evoke rhinitis medicamentosa (Scadding, supra).
A lack of selectivity of currently used sympathomimetics for a specific adrenoceptor subtype raises the possibility that an effective intranasal decongestant could be developed which would not cause rhinitis medicamentosa. For example, several of the imidazoline agonists (e.g. oxymetazoline) possess agonits activity at both alpha.sub.1 - and alpha.sub.2 -adrenoceptors (Minneman, et al., supra). Thus, an agonist selective for alpha.sub.1 -adrenoceptors may not evoke vasoconstriction of nasal mucosa resistance vessels which may be involved in the pathogenesis of rhinitis medicamentosa (Scadding, supra). Similarly, phenylephrine does not discriminate between alpha.sub.1 -adrenoceptor subtypes (Minneman, et al., supra) which have subdivided into alpha.sub.1A -, alpha.sub.1B -, and alpha.sub.1D -adrenoceptor subtypes in the last decade (Ford, et al., Trends Pharmacol. Sci. (1994) 15:167-170). Thus, it is possible that a single alpha.sub.1 -adrenoceptor subtype may selectively mediate vasoconstriction of nasal mucosa venous sinusoids and thus be devoid of adverse effects which could be mediated by other alpha.sub.1 -adrenoceptor subtypes.
Additional Previous Disclosures
Esser, et al., DE 195 14 579 A1 (published Oct. 24, 1996), disclose certain phenylimino-imidazolidine compounds, which are alpha.sub.1L -agonists, for the treatment of urinary incontinence.
Craig, et al., WO 96/38143 (published Dec. 5, 1996), discuss the use of alpha.sub.1C -selective adrenoceptor agonists for the treatment of urinary incontinence.
Purcell, U.S. Pat. No. 4,492,709 (issued Jan. 8, 1985), discloses 2-4(3)-amino-3(4)-hydroxyphenylimino!-imidazoles useful in the treatment of gastric hypersecretion and hyperacidity. A similar disclosure appears in corresponding European application 0 086 126 B1 (published Jul. 24, 1985).
Coquelet, et al., U.S. Pat. No. 4,665,085 (issued May 12, 1987), discuss preparation process and therapeutical application of certain amidines. A similar disclosure is found in European patent application 0 132 190 B1 (published Jan. 13, 1988).
Pesticidal anilinomethylimidazolines are disclosed in Copp, et al., U.S. Pat. No. 4,414,223 (issued Nov. 8, 1983).
Certain imidazolines active as pesticides are discussed in by Copp, et al., Offenlegungsschrift 27 56 638 (published Jun. 22, 1978), and in corresponding Brevet D'Invention No. 862,022 (published Jun. 19, 1978).
Sulfonamides of phenoxyacetic acids and imidazoline derivatives from sulfonamido compounds of phenoxyacetic acid and of cresoxyacetic acids and their hypotensive activity are described by Gh. Botez, et al., in Chemical Abstract 6834 (1964).
Broersma, et al., U.S. Pat. No. 4,343,808 (issued Aug. 10, 1982), disclose the inhibition of sickling of sickle erythrocytes using certain phenoxy-, phenylthio- or anilino-imidazoline compounds.
Reiter, et al., U.K. Patent Application GB 2 160 198 A (published Dec. 18, 1985), discuss certain imidazolines.
Jones, et al., WO 96/17612 A1 (published Jun. 13, 1996), disclose treating cerebral or cardiac ischaemia or convulsions and also sickle cell anemia using new or known phenyl-guanidine or amidine derivatives.
Black, et al., U.S. Pat. No. 4,238,497 (issued Dec. 9, 1980), discloses imidazoline derivatives, salts thereof, and their use as pesticides.
The use of alpha.sub.1A -selective adrenoceptor agonists for the treatment of urinary incontinence is discussed in Craig, et al., U.S. Pat. No. 5,610,174 (issued Mar. 11, 1997).
Prasit, et al., European patent application 0 535 923 A1 (published Apr. 7, 1993), discloses (azaarylmethoxy)indoles as inhibitors of leukotriene biosynthesis.
(Azaaromaticalkoxy)indoles as inhibitors of leukotriene biosynthesis are discussed in Frenette, WO 93/16069 (published Aug. 19, 1993).
Aslanian, et al., U.S. Pat. No. 5,578,616 (issued Nov. 26, 1996), disclose certain phenylalkylimidazoles having pharmacological properties, particularly CNS activities and activity against inflammatory disease.
Morino, et al., U.S. Pat. No. 5,360,822 (issued Nov. 1, 1994), disclose certain sufonanilide derivatives useful as remedies for urinary incontinence.
Wismayr, et al., U.S. Pat. No. 3,340,298 (issued Sep. 5, 1967), disclose certain phenylalkanolamine derivatives useful for treating hypertensive conditions.
Winn, et al., U.S. Pat. No. 4,665,095 (issued May 12, 1987), disclose certain imidazolines useful for treating nasal congestion.
Robertson, et al., U.S. Pat. No. 4,956,388 (issued Sep. 11, 1990), disclose certain 3-aryloxy-3-substituted propanamines capable of inhibiting the uptake of serotonin and norepinephrine.
Gluchowski, et al., U.S. Pat. Nos. 5,403,847 (issued Apr. 4, 1995) and 5,578,611 (issued Nov. 26, 1996), disclose certain .alpha..sub.1C specific compounds useful for treating benign prostatic hyperplasia.
Cupps, et al., U.S. Pat. No. 5,541,210 (issued Jul. 30, 1996), disclose certain benzimidazole compounds useful as .alpha..sub.2 adrenoceptor agonists for treating respiratory, ocular, and/or gastrointestinal disorders.
Bard, et al., U.S. Pat. No. 5,556,753 (Sep. 17, 1996), disclose certain human .alpha..sub.1 adrenegric receptors and uses thereof. See also WO 94/08040 (published Apr. 14, 1994).
Meyer, et al., U.S. Pat. No. 5,597,823 (issued Jan. 28, 1997), disclose certain tricyclic substituted hexahydrobenz(E)isoindone alpha-1 adrenergic antagonists useful for treating benign prostatic hyperplasia.
Jeon, et al., WO 97/31636 (published Sep. 4, 1997), disclose certain indole and benzothiazole derivatives which are selective for cloned human .alpha..sub.2 receptors.
Wong, et al., WO 97/42956 (published Nov. 20, 1997), disclose certain dihydropyrimidine compounds which are selective antagonists for human .alpha..sub.1 receptors.
Jeon, et al., WO 96/04270 (published Feb. 15, 1996), disclose certain benzimidazole derivatives selective for cloned human alpha 2 receptors and which are useful as analgesic, sedative, or anaesthetic agents.